Blood diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.

Gene therapy for monogenic disorders: challenges, strategies, and perspectives

Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.

Paroxysmal Kinesigenic Dyskinesia:Genetics and Pathophysiological Mechanisms

Paroxysmal kinesigenic dyskinesia(PKD),the most common type of paroxysmal movement disorder,is characterized by sudden and brief attacks of choreoathetosis or dystonia triggered by sudden voluntary movements.PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene.The exact pathophysiological mechanisms of PKD remain unclear,although the function of PRRT2 protein has been well characterized in the last decade.Based on abnormal ion channels and disturbed synaptic transmission in the absence of PRRT2,PKD may be channelopathy or synaptopathy,or both.In addition,the cerebellum is regarded as the key pathogenic area.Spreading depolarization in the cerebellum is tightly associated with dyskinetic episodes.Whereas,in PKD,other than the cerebellum,the role of the cerebrum including the cortex and thalamus needs to be further investigated.

Both gain-and loss-of-function variants of KCNA1 are associated with paroxysmal kinesigenic dyskinesia

KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelαsubunit.Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases.Using the whole exome sequencing followed by Sanger sequencing,we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families.The proband of one family(c.496G>A,p.A166T)manifests as episodic ataxia type 1,and the other two(c.877G>A,p.V293I and c.1112C>A,p.T371A)manifest as PKD.The pathogenicity of these variants is confirmed by functional studies,suggesting that p.A166T and p.T371A cause a loss-of-function of the channel,while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected.By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein,we find that these variants tend to cluster around the pore domain,which is similar to epilepsy.Thus,our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype–phenotype correlations of KCNA1 channelopathy.

Perivascular spaces relate to the course and cognition of Huntington’s disease

Huntington’s disease(HD)is an autosomal dominant neurodegenerative disease that is caused by a cytosine-adenine-guanine(CAG)expansion in the first exon of the huntingtin(HTT)gene,which codes for the hun-tingtin protein.It typically manifests with a triad of symptoms,including motor disorders,cognitive impair-ment and psychiatric disturbances[1].HD primar-ily affects the basal ganglia(BG),especially the caudate and putamen,after which it extends to more widespread gray and white matter[2].Perivascular spaces(PVSs)are fluid-filled extensions of the subarachnoid spaces that enclose cerebral blood vessels and extend from the cer-ebral cortex through the brain parenchyma.The physi-ological role of PVSs is the drainage of brain interstitial fluid into perivascular pathways for the elimination of waste products through the glymphatic drainage sys-tem.An increasing number of studies have demonstrated that enlarged PVSs indicate glymphatic dysfunction and are associated with many neurological diseases,such as Alzheimer’s disease,Parkinson’s disease and small vessel disease[3].With the advantage of strong field strengths,7.0 T images show superior resolution and signal-to-noise ratios than 3.0 T,which facilitate the visualization of PVS.And automated segmentation methods could accurately identify PVS in a short time with no inter-rater variability.In the current study,we used U-shaped networks(U-net),a class of deep learning methods,to explore the PVS distribution in HD and controls.To date,PVS distribution in HD is still unclear.Only two studies have investigated PVSs in HD,and both dem-onstrated increased visible PVS burden in manifest HD compared to controls[4,5].However,whether PVS bur-den increases in premanifest HD(pre-HD)individuals remains unknown,and the relationship of PVS with cog-nitive decline has never been studied.

Identifying extracerebellar characteristics in a large cohort of 319 Chinese patients with spinocerebellar ataxia type 3

To the Editor:Spinocerebellar ataxia type 3(SCA3)is the predominant subtype,representing 48-73%of all SCAs in the Chinese population.[1]It primarily manifests as progressive ataxia,characterized by unsteady gait,dysarthria,and limb clumsiness,due to cerebellar and interconnected gray matter damage.Notably,extracerebellar features such as extrapyramidal and oculomotor abnormalities,and spasticity,often remain underrecognized.This complexity can lead to misdiagnosis,underscoring the necessity for a more comprehensive understanding of both cerebellar and extracerebellar symptoms.

Chinese patients with adult onset leukodystrophy caused by CST3 variants

Leukodystrophies represent a group of cerebral white matter disorders that mainly affect axon-glia units.The disorders are clinically diverse and display significant genetic variability.It is challenging to differentiate hereditary leukodystrophies,particularly those that present in adulthood,from acquired leukodystrophies and other genetic disorders,such as multiple sclerosis(MS)or hereditary spastic paraplegia(HSP)(Wei et al.,2021).Over the past few decades,a series of causative genes associated with leukodystrophies have been identified(Kohler et al.,2018).Nevertheless,a significant proportion of patients still lack a precise molecular diagnosis.